Some of the hormones and growth factor pathways that are critical for the development and normal function of target organs, such as the mammary gland and uterus, are also permissive or causal factors in the formation of carcinomas in these organs. Previous studies have shown that elevated levels of serum IGF-1 are associated with increased breast cancer risk. Mammographic density, which is positively associated with breast cancer risk, also correlates with serum IGF-1 levels. Stimulation of mammary IGF-1 levels by growth hormone is critical for mammary gland ductal morphogenesis. We showed that in mice carrying a null mutation for the igf-1 gene the mammary rudiment fails to develop the extensive branching pattern of ducts typical of wild-type mice. IGF-1m/m (midi) mice, which have about one-third the level of mammary IGF-1 mRNA as controls, develop a mammary gland, but have about a 50% reduction in the extent of branching observed in controls. To determine the influence of serum IGF-1 on the mammary phenotype, we examined whole-mounts of this organ from transgenic mice with a specific deletion of liver IGF-1 achieved by Cre/loxP recombinant methodology. These mice have about 25% of the normal serum level of this growth factor without changes in levels of tissue IGF-1 mRNA. The branching frequency of the mammary ducts in these mice was not different from that of controls, indicating that tissue IGF-1 is probably the major determinant of branching morphogenesis in this organ. Variations in tissue level of IGF-1, especially during the window of pubertal development of the mammary ductal tree of females may contribute to differences in mammographic density. We are continuing studies of the role of the IGF-1 receptor/IRS-1 signaling pathway as a mediator of estrogen-induced mitosis in mouse uterine epithelial cells. Kinase activity of cdk-1/cyclin complexes are being evaluated in both IGF-1 and IRS-1 null mutant mice, since hormone-induced mitosis, but not hormone-induced DNA synthesis, was compromised in both mutants. Hormonal carcinogenesis in this organ may require a functional IGF-1R/IRS-1 signaling system. Members of the ErbB receptor family have been shown to be important in the formation and progression of human breast carcinomas. We found phosphorylated ErbB-3 bound to the p85 subunit of PI-3 kinase and transcripts for heregulin-1 alpha, a mammary ligand for ErbB-3, in mouse mammary adenocarcinomas. Some cell lines derived from mouse mammary adenocarcinomas contained both activated ErbB-3 and heregulin mRNA. Out ultimate goal is to assess the importance of this ligand/receptor system in tumorigenesis. Initially, we intend to suppress heregulin synthesis transiently by an antisense or siRNA strategy to determine effects on ErbB levels and activation, related downstream signaling proteins, and cell growth in vitro.